In a study reported in The Lancet Oncology, Turajlic et al found that renal cell carcinomas were characterized by the highest proportion and number of frameshift insertion and deletion (indel) mutations among solid cancers and that these alterations were associated with augmented immunogenicity across cancer types.
Prevalence of Indels
The study included analysis of whole-exome sequencing data from 5,777 solid tumors across 19 cancer types from The Cancer Genome Atlas. Renal cell carcinomas had the highest proportion (0.12 vs median of 0.05 for other cancer types) and number of indel mutations across all cancers (P < 2.2 × 10-16).
Immunogenicity of Derived Neoantigens
In the entire tumor cohort, analysis of tumor-specific neoantigens showed that compared with nonsynonymous single-nucleotide variants, frameshift indels generated approximately threefold more high-affinity neoantigen binders. In an analysis restricted to neoantigens predicted to be mutant-specific binders, the indels generated approximately ninefold more mutant allele-only binders compared with neoantigens derived from the single-nucleotide variants.
In the renal clear cell carcinoma cohort (n = 392), presence of mutant-specific neoantigens was associated with upregulation of antigen presentation genes, which was correlated with T-cell activation (r = 0.78). Analysis of data from three separate melanoma cohorts treated with immune checkpoint inhibitors indicated that frameshift indel count was significantly associated with response to treatment (P = 4.7 × 10-4).
The investigators concluded: “Renal cell carcinomas have the highest pan-cancer proportion and number of indel mutations. Evidence suggests indels are a highly immunogenic mutational class, which can trigger an increased abundance of neoantigens and greater mutant-binding specificity.”
The study was funded by Cancer Research UK, the UK National Institute for Health Research at the Royal Marsden Hospital National Health Service Foundation Trust, the Institute of Cancer Research and University College London Hospitals Biomedical Research Centres, and others.
Charles Swanton, FRCP, of The Francis Crick Institute, London, is the corresponding author of The Lancet Oncology article.
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